Predicting bacterial resistance using the time inside the mutant selection window: Possibilities and limitations

The time inside the mutant selection window (TMSW) has been shown to be less predictive of selection of fluoroquinolone-resistant bacteria than the ratio of the area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC). To explore the different predictive powers of TMSW and AUC/MIC, enrichment of ciprofloxacin-resistant mutants of four Escherichia coli strains was studied in an in vitro dynamic model at widely ranging TMSW values. Each organism was exposed to twice-daily ciprofloxacin for 3 days. Peak antibiotic concentrations were simulated to be close to the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC, with TMSW varying from 0% to 100% of the dosing interval. Amplification of resistant mutants was monitored by plating on medium with 8× MIC of the antibiotic. For each organism, TMSW plots of the area under the bacterial mutant concentration-time curve (AUBCM) exhibited a hysteresis loop: at a given TMSW that corresponds to the points on the ascending portion of the bell-shaped AUBCM-AUC/MIC curve [when the time above the MPC (T>MPC) was zero], the AUBCM was greater than at the same TMSW related to the descending portion (T>MPC > 0). A sigmoid function fits these separate data sets well for combined data with the four organisms (r2 = 0.81 and 0.92, respectively), in contrast to fitting the whole data pool while ignoring the AUC/MIC-resistance relationship (r2 = 0.61). These data allow the appropriate use of TMSW as a predictor of bacterial resistance.